Alcohol abuse and its related consequences together with HIV/AIDS are the major health problems in many parts of the world. Chronic alcohol use has been found to impair various immune functions, thereby making the body more susceptible to invading pathogens. Based on the several studies in the literature that alcohol consumption leads to immunological deterioration, we hypothesize that alcohol use may exacerbate HIV infection and also accelerate the onset of clinical disease. This is a complex research issue and, to date, there are no clear answers in this regard. The prospect of testing proof-of-concept studies regarding correlation between alcohol consumption and disease in HIV-positive humans is untenable because of variable incubation periods and long length time that are required to address this important issue. Furthermore it is not known whether alcohol abuse will adversely affect the vaccine-induced immune response and it will confer inferior protection after natural infection. The latter issue becomes more important because several HIV candidate vaccine are in various phase of clinical trial. The present application is designed to address these vital questions in SHIVKU/macaque model of AIDS. This model of HIV/AIDS has been successfully used in our laboratory to study the pathogenesis of the virus, effect of anti retroviral drugs and evaluation of different candidate vaccines. In this proposal we will test the hypotheses in four specific aims. The experiments in Aim-1 will examine the effect of alcohol on co-receptor expression and replication of SIV and SHIV(s). We will also examine the effect of alcohol on NFkb activation, and whether suppressing NFkb activation can modulate virus replication. The proposed experiments in Aim-2 deal with establishment of a SHIV/macaque model of alcohol dependence and examine whether alcohol consumption accelerates the onset of SHIV-induced AIDS in macaques. In Aim 3 and 4, we will examine the effect of chronic alcohol consumption on development and persistence of a live attenuated vaccine-induced immune responses and whether challenge with a pathogenic SHIV confers inferior protection in alcohol-dependent macaques. These studies will help us not only to understand pathogenesis of the SHIVKU in alcohol abuse set-up, but also whether chronic alcohol abuse compromises vaccine-induced development and persistence of virus-specific immune responses and vaccine mediated protection after pathogenic challenge. [unreadable] [unreadable]